Department of Biochemistry and Molecular Biology, and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, VIC 3010, Australia.
Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St Louis, MO 63130, USA.
J Mol Biol. 2018 May 11;430(10):1442-1458. doi: 10.1016/j.jmb.2018.03.031. Epub 2018 Apr 5.
Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington's disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild-type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen-deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ regions and the tail encompassing the C-terminal proline-rich region. The surface area of the globular domain increases monotonically with polyQ length. This stimulates sharp increases in gain-of-function interactions in cells for expanded polyQ, and one of these interactions is with the stress-granule protein Fus. Our results highlight plausible connections between Httex1 structure and routes to neurotoxicity.
可溶性亨廷顿病外显子 1（Httex1）与扩展的聚谷氨酰胺（polyQ）结合产生神经毒性。为了揭示这种毒性的物理基础，我们对野生型和突变型 polyQ 长度的可溶性 Httex1 进行了结构研究。核磁共振实验表明，polyQ 区域存在构象刚性。相比之下，氢氘交换实验表明没有酰胺保护，表明氢键几乎不存在。这些看似矛盾的结果可以通过全原子模拟来解释，该模拟表明 Httex1 采用了类似蝌蚪的结构，球状头部包含 N 端的两亲性和 polyQ 区域，尾部包含 C 端富含脯氨酸的区域。球状结构域的表面积随 polyQ 长度呈单调增加。这刺激了扩展的 polyQ 在细胞中功能获得性相互作用的急剧增加，其中一种相互作用是与应激颗粒蛋白 Fus。我们的研究结果突出了 Httex1 结构与神经毒性途径之间的可能联系。
